Immunoinflammatory disorders (e.g., rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, stroke-induced brain cell death, ankylosing spondylitis, fibromyalgia, and inflammatory dermatoses, asthma, multiple sclerosis, type I diabetes, systemic lupus erythematosus, scleroderma, systemic sclerosis, and Sjögren's syndrome) are characterized by dysregulation of the immune system and inappropriate activation of the body's defenses, resulting in damage to healthy tissue.
One percent of humans world-wide are afflicted with rheumatoid arthritis (RA), a relentless, progressive disease causing severe swelling, pain, and eventual deformity and destruction of joints. According to the Arthritis Foundation, rheumatoid arthritis currently affects over two million Americans, of which women are three times more likely to be afflicted. Rheumatoid arthritis is characterized by inflammation of the lining of the joints and/or other internal organs, and the presence of elevated numbers of lymphocytes and high levels of proinflammatory cytokines.
Diagnosis of RA generally includes: (i) morning stiffness in joints lasting at least one hour before improvement, (ii) arthritis of three or more joint areas having simultaneously soft tissue swelling or fluid; (iii) arthritis of at least one hand joint; (iv) symmetric arthritis, i.e., simultaneous involvement of the same joint area on both sides of the body; (v) rheumatoid nodules; (vi) abnormal serum rheumatoid factor; and (vii) radiographic changes typical of rheumatoid arthritis on posteroanterior hand and wrist radiographs, which include erosions or unequivocal bony decalcification localized in or most marked adjacent to the involved joints. Patients are classified as having RA if at least four of these seven criteria, and (i) through (iv) must have been present for at least six weeks. (American College of Rheumatology, 1987 Criteria for the Classification of Acute Arthritis of Rheumatoid Arthritis, based on Arnett F C et al., Arthritis Rheum. 1988; 31:315-324). Pain per se is not required for the diagnosis of RA.
Treatment of RA generally includes anti-inflammatory strategies directed at suppressing the clinical manifestations of joint inflammation, including synovial thickening, joint tenderness, and joint stiffness. Drugs used to address these signs and symptoms generally include (i) non-steroidal anti-inflammatory drugs (NSAIDs; e.g., detoprofen, diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenameate, mefenamic acid, meloxicam, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmetin, celecoxib, rofecoxib, aspirin, choline salicylate, salsalte, and sodium and magnesium salicylate)—these drugs may be adequate for mild RA, but do not appear to alter the longterm course of the disease; and (ii) steroids (e.g., cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone).
Treatment for RA may also include strategies directed at limiting the long term joint damage and deformity caused by the inflammation in the joints. Such treatments are generally described as DMARDs, i.e., disease modifying antirheumatic drugs (e.g., cyclosporine, azathioprine, methotrexate, leflunomide, cyclophosphamide, hydroxychloroquine, sulfasalazine, D-penicillamine, minocycline, gold, etanercept (soluble TNF receptor) and infliximab (a chimeric monoclonal anti-TNF antibody)).
There is a need to develop new regimens for the treatment of immunoinflammatory disorders.